Chemistry and Drug Metabolism Pharmacokinetics (DMPK) Core
The Chemistry/DMPK Research Core is designed to provide lead optimization, analytical/bioanalytical expertise, drug metabolism (DM), pharmacokinetics (PK) and pharmacodynamics (PD) expertise on natural products and related compounds that are determined by the CORE-NPN investigators to have significant biological activity in the In Vitro and In Vivo Pharmacology Cores. This may include semi-synthesis of lead natural products to generate data on structure-activity-relationships (SAR) and metabolism-activity-relationships (MAR) to optimize the drug candidates. For pure isolates where there is not enough material to conduct full pharmacological testing, the Chemistry/DMPK Core will synthesize larger quantities of the active components for in vitro and in vivo studies. In addition, the Core will make available the bulk-synthesis of compounds that have potential clinical usefulness. The Chemistry/DMPK Core will also have an advisory role for the CORE-NPN investigators that require expertise in the area of exploration of SAR and MAR, analytical method development and validation, chemical modifications to influence PK properties, and pharmaceutical and chemical influences on solubility and formulation, and PK/PD analysis.
Chemistry and Drug Metabolism Pharmacokinetics Core Services
* Total cost will depend on the number of personnel hours required and consumable cost/instrument time as applicable.
* Please contact the core director for a quote: Dr. John Rimoldi at firstname.lastname@example.org or 662-915-5119.
Synthesis and Purification
We specialize in milligram to gram scale synthesis of small and large organic molecules including medicinal compounds, peptides, polymer-drug conjugates (for targeted drug delivery), Biometabolites (as reference standards), Lead molecule editing and analog synthesis; Semi-synthesis of natural products, Extraction and isolation of natural products. Purification of crude extracts from natural or synthetic sources by chromatography.
LC-MS (low resolution analysis) Purity Assessment
Mass analysis of the compounds by electrospray method
Percentage estimation of Carbon, Hydrogen, Nitrogen in the compounds
Bioanalytical Method Development and Validation HPLC/UPLC/MS-MS
Literature review of generic molecules, Physicochemical properties of the compound, compound optimization in MS/MS, method optimization using UPLC/MS-MS, Optimize the extraction method, Optimize the lower limit of quantitation (LLOQ), trial precision and accuracy batch. Specificity, Selectivity, Matrix effect, recovery, Intra- and inter-day precision and accuracy batches, various stability studies etc.
To analyze the drug and metabolite concentrations from various biological fluids (plasma, blood, urine, feces and various tissues etc).
Pre-Clinical PK Studies Per Compound Single Dose (8 timepoints; N=3, mice/rat)
To identify the key pharmacokinetic parameters like half-life, Cmax, AUC, CL, Vd, %F, the compound should be administered orally, intraperitoneal, subcutaneous and intravenous routes, respectively. After the compound administration plasma/blood will be collected at various pre-determined time points and analyzed by using UPLC-MS/MS.
Tissue Distribution Accumulation (three time point; N=3, mice)
Drug distribution/accumulation into major organs, the brain in particular, will be evaluated by monitoring the drug concentrations in the tissue homogenates. Mice or rats will be sacrificed at the pre-determined time points. Typically brain, liver, lung, spleen, kidney and heart will be harvested. To quantify the drug levels, tissue homogenates will be extracted and analyzed by validated LC-MS/MS methodologies. Tissue:plasma ratios of drug levels at various time points will be determined as an indicator for various tissue permeability.
In Vitro Metabolism Studies - Liver Microsomes
Understand the metabolism of your compounds by using our microsomal stability assay to measure in vitro intrinsic clearance (CLint) or to identify metabolites formed or half-life (T1/2) or percentage degradation of the compound at the pre-determined time points.
In Vitro Metabolism Studies - Liver Homogenates
Understand the metabolism of your compounds by using our liver homogenate stability assay to measure the percentage metabolism of the compound at the pre-determined time points.
Physicochemical Characterization Per Compound
1. Structural Characterization by multinuclear NMR spectroscopy (500 MHz: 1H, 13C, NOSEY); Fourier-transform infrared (FTIR) spectroscopy; Optical rotation
2. Solubility study and Chemical stability